SK106595A3 - Substituted derivatives of 4-phenyl-6-amino-nicotinic acid, mnufacturing process thereof, drugs containing these substances and their use - Google Patents

Abstract

The use of substd. 4-phenyl-6-aminonicotinic and derivs. of formula (I) and their salts is claimed for therapeutic purposes. A = 6-10C aryl or pyridyl (both opt. mono- to tri-substd., by NO2, CN, phenyl, halo, CF3, 1-6C alkylthio and/or 1-6C alkoxy); Y = CN or NO2; R1 = H or 1-8C alkyl; R2, R3 = H, 1-6C alkyl or 1-6C acyl. Cpds. (I) are new, except for the ethyl esters of 6-amino-5-cyano-2-methyl-4-phenylnicotinic acid, 6-amino-4-(4-chlorophenyl)-5-cyano-2-methyl nicotinic acid, 6-amino-5-cyano-2-methyl-4-(4-methoxyphenyl)-nicotinic acid and 6-amino-5-cyano-2-methyl-4-(4-nitrophenyl)-nicotinic acid.

Description

Technical field

The invention relates to the use of partially known substituted 4-phenyl-6-amino-nicotinic acid derivatives as medicaments, novel active compounds, a process for their preparation and their use as potassium channel modulators, in particular for the treatment of the central nervous system.

BACKGROUND OF THE INVENTION

From publications (Collect. Czech. Chem. Commun. 56, (10), 2175)

2182, 1991 and Khim. Geterotsikl. Soedin. (11), 1504-508,

1984), some 4-phenyl-3-pyridine-carboxylic acid derivatives are known, and no pharmacological effect is described herein.

SUMMARY OF THE INVENTION

It has now been found that substituted acid derivatives

4-Phenyl-6-amino-nicotinic compounds of formula I

in which

A represents an aryl group having 6 to 10 carbon atoms or a pyridyl group optionally substituted up to three times equally or differently with cyano, nitro, halogen, trifluoromethyl or a straight or branched alkylthio or alkoxy of up to 6 carbon atoms.

R ¹ represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,

R ² and R ³ are the same or different and are H or straight or branched alkyl or acyl having up to 6 carbon atoms and

D is nitro or cyano and their salts surprisingly have a large potassium channel effect and are therefore suitable for use as medicaments, particularly as agents for the treatment of cerebral sickle cell anemia.

Preferred salts are physiologically acceptable salts. These are generally salts of the compounds of the present invention with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic or sulfonic acids such as acetic acid, maleic acid, fumaric acid, acid malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

The compounds of the present invention exist in stereoisomeric forms which behave either as image and mirror image (enantiomers) or not as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms as well as to the mixtures of diastereomers. Like the diastereomers, the racemic forms can be resolved into stereoisomerically uniform moieties by known methods.

For the treatment of cerebral diseases, compounds of the formula I are preferred

A represents a phenyl or naphthyl group, which is optionally up to three times the same or differently substituted by nitro, cyano, fluorine, chlorine, bromine or iodine, trifluoromethyl, phenyl or straight or branched alkylthio or alkoxy of up to 4 carbon atoms .

R ¹ represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R ² and R ³ are the same or different and are H or a linear or branched alkyl or acyl having up to 4 carbon atoms and

D is cyano or nitro and salts thereof.

Particularly preferred for the treatment of cerebral diseases are compounds of formula I wherein:

A represents a phenyl group which is optionally up to two times the same or differently substituted by nitro, cyano, fluorine, chlorine, bromine or iodine, phenyl, trifluoromethyl, methylthio or methoxy,

R ¹ represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R ² and R ³ are the same or different and represent a hydrogen atom or a straight or branched alkyl or acyl group of up to 3 carbon atoms in each case, and

D is cyano or nitro and salts thereof.

The compounds of the present invention are calcium-dependent channel modulators with selectivity for high conductivity (Bk (Ca) -channel) channels, particularly in the central nervous system.

By virtue of their pharmacological properties, the compounds of the present invention can be used for the manufacture of medicaments for the treatment of central degenerative diseases, such as the occurrence of dementia (Multiinfarktdemenz (MID), primary degenerative dementia (PDD), presenile and senile dementia of Alzheimer's disease, HIV-dementia). and other forms of dementia), Parkinson's disease or, amyotrophic lateral sclerosis as well as multiple sclerosis.

The following are active substances suitable for the treatment of brain performance disorders in old age, brain organic psychosyndrome (HOPS) and age-related memory impairment (AAMI).

They are suitable for the prophylaxis and treatment of the consequences of cerebral vascular disorders such as cerebral ischemia, cases of stroke, treatment-cerebral trauma and subarachnoid haemorrhage.

Furthermore, they are valuable for application in depression and psychoses, for example schizophrenia. In addition, they are suitable for application in neuroendocrine secretion disorders, as well as neurotransmitter secretions and associated medical disorders such as mania, alcoholism, drug addiction, zealousness or disease access to food. Other applications include the treatment of migraines, sleep disorders and neuropathies. They are also suitable as painkillers.

The active compounds are furthermore suitable for the treatment of immune system disorders, in particular T-cell proliferation and for affecting smooth muscle, especially the uterus, bladder and bronchial tract, and for the treatment of related diseases such as asthma, urinary incontinence and for the treatment of arrhythmias, angina and diabetes.

The present invention also relates to novel compounds of formula I.

in which A, D, R ¹ , R ² and R ^{3 are} as defined above, with the exception of the following compounds:

6-Amino-5-cyano-2-methyl-4-phenyl-nicotinic acid ethyl ester, 6-amino-4- (4-chlorophenyl) -5-cyano-2-methylnicotinic acid ethyl ester, 6-amino-5- ethyl ester cyano-2-methyl-4- (4-methoxyphenyl) nicotinic acid and 6-amino-5-cyano-2-methyl-4- (4-nitrophenyl) nicotinic acid ethyl ester.

The invention preferably relates to novel compounds of formula Ia

and the salts thereof, wherein the meanings of the substituents are given in the following table:

X, Y R ² R ³ D 4-CF ₃ , H H H NO. 2-C. 3-Cl H H no. H, H H H NO. 3-Cl, 4-CF ₃ H H NO. 3-NO ₂ , H H H NO. 2-CF ₃ , H H H no ₂ 3-Cl, H H H no ₂ 2-Cl, 3-Cl H H no ₂ 2-Cl, 3-Cl H H no ₂ 4-OCH3 _> H H H no ₂ 4-CN, H H H no ₂ 3-Cl, H H H no ₂ 2-CF ₃ , 3-H co-ch ₃ co-ch ₃ no ₂ 2-Cl, 3-Cl ch ₃ H no ₂ Η, Η ch ₃ H no ₂ 3-Cl, 4-CF ₃ ch ₃ H no ₂ 4-CF ₃ , H ch ₃ H no ₂ 3-NO ₂ H ch ₃ H no ₂ 2-CF ₃ , H ch ₃ H no ₂ 2-Cl, 3-Cl co-ch ₃ H no ₂ H, H -co-ch ₃ H no ₂ 2-CF ₃ , 3-H -co-ch ₃ H no ₂ 2-Cl, 3-Cl H H CN _3-NO2, H H H CN

Ί

X, Y R ² R ³ D H, H H H CN 2-CF ₃ , H H H CN 4-Cl, H H H CN 2-CF ₃ , H H H CN 4-C ₆ H ₅₎ H H H CN 2-Cl, 3-Cl -coch ₃ H CN 3-NO, H -coch ₃ H CN 2-CF _3> H -coch ₃ H CN 4-CF ₃ H -coch ₃ H CN 2-Cl, 3-Cl ch ₃ H CN _3-NO2, H ch ₃ H CN 2-CF ₃ , H ch ₃ H CN 4-Cl, H ch ₃ H CN 4-CF ₃ , H ch ₃ H CN H, H ch ₃ H CN

and

The novel compounds of the formula I are prepared by reacting the dihydropyridines of the formula II

H (Π) in which A, D, R ¹ , R ² and R ^{3 are} as defined above and a

R < ⁴ > is as defined for R < ¹ & gt ^; and R < ¹ > but does not represent a hydrogen atom;

The process of the present invention is illustrated by the following reaction scheme:

possible example

NaHZCH ₃ J —-->

DMF

Suitable solvents are all inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethyl alcohol, propanol or isopropyl alcohol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, acetonitrile, amides such as hexamethylphosphoric triamide, acetic acid, dimethylformamide, hydrocarbons such as methylene chloride and carbon tetrachloride, or hydrocarbons such as benzene or toluene. It is also possible to use mixtures of the solvents mentioned. Methylene chloride is particularly preferred.

As solvents for oxidation, organic solvents which do not change. These preferably include methanol, ethyl alcohol, ethers such as, for example, all inert reaction conditions with alcohols such as propyl alcohol or isopropanol, diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, acetonitrile, amides such as trimethylphosphoric triamide dimethylformamide, acetic acid, halogenated hydrocarbons such as methylene chloride and carbon tetrachloride, or hydrocarbons such as benzene or toluene. Mixtures of solvents may also be used. Methylene chloride is particularly preferred.

2,3-Dichloro-4,5-dicyano-p-benzoquinone and its derivatives, pyridinium dichromate, elemental bromine and iodine and manganese dioxide are generally suitable. Manganese dioxide is preferred.

Oxidizing agents the generally used in in an amount of from 1 mol to 1 mol 20 mol, preferably 1 of formula II. M up to 5 moles, relative per mole of compound Reaction temperatures the can move in wide range. Work is generally in progress at the temperature in the range 10 'C to 150' C,

preferably 20'C to 100'C, especially at room temperature.

The processes can be carried out at normal, elevated or reduced pressure (e.g., in the range 0.05 to 0.3 MPa), preferably at normal pressure.

Suitable solvents for the alkylation are also customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as dioxane, tetrahydrofuran or, for example, or dimethylformamide, diethyl ether, acetonitrile, amides, hexamethylphosphoric, acetic, halogenated hydrocarbons, trichloromethane, carbon tetrachloride, glycol dimethyl ether, triamide, ethyl ester of the acid such as dichloromethane; trichlorethylene or chlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, triethylamine, pyridine, dimethylsulfoxide, acetone or nitromethane. Mixtures of the abovementioned solvents may also be used. Dimethylformamide is particularly preferred.

Suitable bases are, in general, alkali metal hydrides or alcoholates, such as sodium hydride or potassium tert-butylate, or cyclic amines, such as piperidine, dimethylaminopyridine and C 1 -C 4 alkyl amines, such as triethylamine. Sodium hydride is particularly preferred. The reaction temperatures can be varied within a wide range. In general, the reaction is carried out in the range from 10 ° C to 150 ° C, preferably 20 ° C to 100 ° C, and in particular at room temperature.

The alkylation is carried out in the abovementioned solvents at a temperature in the range of 0 ° C to 150 ° C, preferably at room temperature to 100 ° C.

The reactions can be carried out at normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.05 to 0.3 MPa. Usually, it is operated under normal pressure.

The bases are generally used in an amount of 1 to 5 mol, preferably 1 to 2 mol, in each case based on 1 mol of alkylated compound.

Suitable bases for alkylation are inorganic or organic bases. These preferably include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as e.g. calcium carbonate, or organic amines, for example trialkylamines having 1 to 6 carbon atoms in alkyls such as triethylamine, and heterocycles such as pyridine, methylpiperidine or morpholine. Triethylamine is particularly preferred.

Suitable solvents for the acylation are also customary inert organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene or chlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, hexane, hexane, hexane, fractions and further ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible for solvents or the corresponding solvent. Particular preference is given to a pyridine.

using mixtures of the acylating agent mentioned as acetic anhydride

The acylation is generally carried out at a temperature of 0 ° C to 120 ° C, preferably at a temperature of 30 ° C to 90 ° C and under normal pressure.

'C

The saponification of carboxylic acid esters is carried out by conventional methods by treating the ester in inert solvents with the usual bases).

Suitable bases for saponification are the customary inorganic bases.

These preferably include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide or alkali metal carbonates such as sodium carbonate or potassium carbonate. Sodium hydroxide and potassium hydroxide are particularly preferred.

Suitable solvents for the saponification are water or the usual organic solvents for saponification. These preferably include alcohols such as methanol, ethyl alcohol, propyl alcohol, isopropyl alcohol or butyl alcohol, or ethers such as tetrahydrofuran or dioxane, but also dimethylformamide and dimethylsulfoxide. Particularly preferred are alcohols such as methanol, ethyl alcohol, propanol or isopropyl alcohol. It is also possible to use mixtures of the solvents mentioned.

The saponification is generally carried out at a temperature in the range of 0 ° C to 100 ° C, preferably at 20 ° C to 80 ° C.

The reactions can be carried out at normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

Enantiomerically pure forms are obtained, for example, by separating diastereomeric mixtures of compounds of formula I and Ia in which R 1 / R 1 is an optically active ester moiety by conventional methods, then either directly re-esterifying or first producing chiral carboxylic acids and then esterifying with the corresponding alcohols to produce enantiomerically pure compounds.

The separation of the diastereomers is generally carried out either by fractionated crystallization, by column chromatography or by Craig separation. The optimum method must be determined on a case-by-case basis, but it is often useful to use combinations of individual procedures. Particular preference is given to crystallization or Craig separation, or a combination of both.

Enantiomerically pure compounds are also available by chromatography of racemic esters on chiral phases.

The compounds of formula (II) are known or can be prepared by reacting compounds of formula (III)

(ΙΠ) in which A and R ⁴ as hereinbefore defined, with compounds of formula IV ^R2R3N \ / ^NH2 (IV) telephone which R, R and D have the meaning indicated in one of the abovementioned organic solvents, preferably ethyl alcohol , optionally in the presence of a base.

Suitable bases are generally alkali metal hydrides or alcoholates, such as sodium hydride or tertiary. potassium butylate, or cyclic amines such as piperidine, dimethylaminopyridine or C 1 -C 4 alkyl amines such as triethylamine. Preferred are piperidine, dimethylaminopyridine, pyridine, sodium hydride and tert.

sodium butylate.

The bases are generally used in an amount of 1 to 5 mol, preferably 1 to 2 mol, based on 1 mol of the compound of the general formula

III.

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out at a temperature between 10 ° C and 150 ° C, preferably at 20 ° C and 100 ° C, especially at the boiling point of the solvent used.

The reactions can be carried out at normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.05 to 0.3 MPa. Usually, it is operated under normal pressure.

The compounds of the formulas III and IV are known or can be prepared by customary methods.

The present invention also relates to pharmaceutical compositions which contain inert, non-toxic and pharmaceutically acceptable excipients and carriers containing one or more compounds of the general formula I / Ia, or consisting of one or more such active ingredients as well as a process for the preparation of such compositions.

The active compounds of the formula I / Ia are present in these compositions in concentrations of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, based on the total mixture.

In addition to the active compounds of the formula I / Ia, the pharmaceutical compositions can also contain other pharmaceutical active compounds.

The above pharmaceutical preparations can be prepared by conventional methods according to known methods, for example using an excipient or substances and a carrier or carriers.

In general, it has proven advantageous to administer the active compounds of the formula I / Ia in a total amount of about 0.01 to 100 mg / kg, preferably about 1 mg / kg to 50 mg / kg of body weight per 24 hours, optionally in an amount in the form of several individual doses.

It may be advantageous to dispense with the above-mentioned amounts, depending on body weight or type of administration, the degree of the disease, but also on individual tolerance to the medicament, the type and type of preparation, and the time or interval at which application ongoing.

The evaluation of the effect is carried out using the following test:

⁸⁶ Rubidium-efflux from C6-BU1-glioma cells

The experiments were carried out with slight changes according to the method described by Tas et al. (Neurosci. Lett. 94, 279-284, (1988)). Rat C6-BU1-glioma cells are used for this.

From the data, the efflux-induced increase in baseline efflux is calculated and determined to be 100%. Stimulation in the presence of test substances then refers to this value.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example I

6-Amino-4- (3-chloro-4-trifluoromethylphenyl) -1,4-dihydro-2-methyl-5-nicotinic acid methyl ester

Cl, NO ₂ NH ₂

(3-Chloro-4-trifluoromethylbenzylidene) -acetoacetic acid methyl ester (15.3 g, 50 mmol) and 5.2 g (50 mmol)

2-nitro-1,1-ethanediamine (prepared according to R. Troschutz, A. Luckel, Ar. Pharm. (Weinheim) (324, 73-77 (1991))) is dissolved in 80 ml of ethyl alcohol and left for 12 hours at room temperature. reflux. After cooling, the resulting solid was filtered off with suction and washed with ethyl alcohol. 13.0 g (66% of theory) of the title compound are obtained.

Mp: 250 ° C

Example II

6-Acetylamino-4- (3-chloro-4-trifluoromethylphenyl) -1,4-dihydro-2-methyl-5-nitronicotinic acid methyl ester

4.0 g (12.0 mmol) of the compound of Example 1 are dissolved in 40 ml of acetic anhydride and heated at reflux for 12 hours. Acetic anhydride is then distilled off under reduced pressure, the residue is dissolved in dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate, concentrated and the residue is purified by chromatography on silica gel (toluene / ethyl acetate / isopropyl alcohol 100: 10: 1). The concentrated eluate was crystallized from ethanol to give 0.5 g (11% of theory) of the title compound.

MP: : 152 ° C.

Example III

6-Amino-5-cyano-2-methyl-4- (trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester

13.6 g (50 mmol) of methyl ester

2-acetyl- (4-trifluoromethyl-phenylacetic acid), 7.45 g (50 mmol) of cyanoacetimidic acid ethyl ester hydrochloride and 15 g (190 mmol) of ammonium acetate are heated to reflux in 100 ml of methanol for one hour. The organic phase is washed twice with dilute sodium hydrogen carbonate solution and once with water, dried over sodium carbonate and concentrated in vacuo. 3 g (37% of theory) of colorless crystals.

T. t. : 210 -214 ’C.

Example IV

6-Acetamido-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid methyl ester

6.7 g (20 mmol) of 6-amino-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid methyl ester (prepared according to Example III) and 33.5 ml (350 mmol) of acetic anhydride was heated to reflux for 30 minutes. The excess acetic anhydride is then reacted to give methyl acetate at 25 ° C by addition of methanol. The reaction solution was then evaporated in vacuo and stripped twice with toluene in vacuo. The residue is then boiled with 50 ml of toluene and the precipitated crystals are filtered off and washed with toluene.

Yield: 3.6 g (50% of theory)

mp: 224 ’C (decomposition).

Example V

5-Cyano-4- (2,3-dichlorophenyl) -2-methyl-6-N-methylamino-1,4-dihydropyridine-3-carboxylic acid methyl ester

ch ₃ h

2.8 g (10 mmol) of 2-acetyl- (2,3-dichlorophenyl) -acetic acid methyl ester and 1.5 g (10 mol) of cyanoacetimidic acid ethyl ester hydrochloride are mixed with 5 ml of a 33% ethanolic methylamine solution (40 mmol). . The reaction mixture is heated to 46 ° C and, after cooling to 30 ° C, 2.3 ml (40 mmol) of glacial acetic acid are added, followed by 20 ml of methanol. After refluxing for 5 hours, the reaction solution was mixed with ice water and extracted with ethyl acetate. After drying the organic phase over sodium sulfate and concentrating under reduced pressure, 3.9 g of an amorphous residue are obtained which is chromatographed on 100 g of silica gel using a toluene / ethyl acetate mixture (gradient).

Yield: 0.5 g (10% of theory) (crystals)

mp: 234-239 ° C

Production examples

Example 1

6-Amino-2-methyl-5-nitro-4- (4-trifluoromethylphenyl) -nicotinic acid methyl ester

2.0 g (5.6 mmol) of 6-amino-2-methyl-5-nitro-4- (4-trifluoromethyl-1,4-dihydronicotinic acid methyl ester (prepared as described in Example I)) was dissolved in 100 mL of methylene chloride and mixed. The reaction mixture is stirred for 12 hours at room temperature, then the batch is filtered through silica gel (methylene chloride), the filtrate is concentrated and the residue is crystallized from methanol. 1.4 g (70% of theory) of the title compound.

M.P. : 185-186 “C.

Analogously to Example 1, the compounds shown in Table 1 are prepared:

Table 1

^O 2 ^N / J / ^CO 2 ^{CH 3}

Η ₂ Ν ^χΛ ^ Ν ' ^Λ 0Η ₃

Pr. X Y Výthžzk (% theor.) 1.1. (° C) 2 H H 70 202-4 3 3-Cl 4-CF ₃ 33.5 210-2 4 2-Cl 3-Cl 70 178-9 5 3-NO ₂ H 96 175-77 6 2-CF ₃ H 41 191 7 3-Cl 4-C1 62 202-3 8 2-Cl 3-Cl 92 149-50 (-) - The enantiomeric. 9 2-Cl 3-Cl 90 149-50 (+) - The enantiomeric. 10 4-OCH ₃ H 25 197 11 4-CN H 68 205-6 12 3-Cl 2-CN 5 236-9

Example 13

6-N, N-diacetylamino-2-methyl-5-nitro-4- (2-trifluoromethylphenyl) -nicotinic acid methyl ester

0.8 g (2.25 mmol) of the compound of Example 6 was dissolved in 20 ml of acetic anhydride and the mixture was heated at reflux overnight. After distilling off the acetic anhydride, the crystalline residue is washed with water and recrystallized from ethyl alcohol. 250 mg (28% of theory) of the title compound are obtained.

MP: : 113 ’C.

Example 14

4- (2,3-Dichlorophenyl) -2-methyl-6-N-methylamino-5-nitronicotinic acid methyl ester

0.7 g (2 mol) of the compound of Example 4 was dissolved in 20 ml of dried DMF and treated with 70 mg (80%) of sodium hydride. After stirring at room temperature for 3 hours, the reaction mixture was treated with 2.5 ml of a 1M solution of methyl iodide in dimethylformamide and stirred again for 18 hours at room temperature. Concentration and filtration through silica gel (ethyl acetate / toluene 1:10) gave 0.8 g of crude product, which was purified by column chromatography (ethyl acetate / toluene 1:80). 65 mg of product (9% of theory) are obtained.

Analogously to Example 14, the compounds listed in Table 2 were prepared:

Table 2

Pr. X Y Yield (%) mp (° C) 15 H H 20 123-4 16 3-C1 4-CF ₃ 70 148 17 4-CF ₃ H 56 137-8 18 3-NO ₂ H 23 196-7 19 2-CF ₃ H 20 110-1

Example 20

6-N-Acetylamino-4- (2,3-dichlorophenyl) -2-methyl-5-nitronicotinic acid methyl ester

CH ₃

800 mg (2 mmol) of methyl 6-N-acetylamino-4- (2,

3-Dichlorophenyl) -1,4-dihydro-2-methyl-5-nitronicotinic acid (prepared according to Example II) is dissolved in 80 ml of methylene chloride, mixed with 5 g of manganese dioxide and stirred for 3 hours at room temperature. After filtration through celite and column chromatography (ethyl acetate / toluene 4: 1), the concentrated eluate is recrystallized from toluene. 303 mg (38% of theory) of the title compound are obtained.

MP: : 195 C.

Analogously to Example 20, the compounds listed in the following Table 3 were prepared:

Table 3

X

Pr. X Y Výtíažck (% theory) 1.1. (° C) 21 H H 19 178-9 22 2-CF ₃ H 64 141-2

Example 23

6-Amino-5-cyano-4- (2,3-dichlorophenyl) -2-methyl nicotinic acid methyl ester

1.0 g (3 mmol) of 6-amino-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydronicotinic acid methyl ester (prepared according to Example III) and 2.6 g (30 mmol) The manganese dioxide was stirred in 20 ml of methylene chloride for 70 hours at room temperature. The solvent was then stripped off in vacuo and the residue was mixed with ethyl acetate and filtered through silica gel. 0.6 g (60% of theory) of the title compound is obtained as colorless crystals.

Mp: 251-253 ° C.

Example 24

6-Amino-5-cyano-4- (3-nitrophenyl) -2-methylnicotinic acid methyl ester

The title compound was prepared analogously to Example 20.

Rf = 0.19 (toluene / ethyl acetate 3: 1) m.p. : 202 - 205 ´C Yield: 80% of theory.

Analogously to Examples 23 and 24, the compounds listed in Table 4 are prepared:

Table 4

CO ₂ CH ₃

H ₂ N 4 N 1 CH,

Pr. X, Y Mining (% theory) 1.1. (° C) 25 H, H 55 254-8 26 2-CF ₃ , H 45 212 27 4-Cl, H 65 231 28 4-CF ₃₎ H 85 201-5 29 4-C ₆ H _5j 38 241-4

Example 30

6-Acetamido-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid methyl ester

Analogously to Example 23, 4.3 g (11 mmol) of the compound of Example IV were oxidized with 10.7 g (120 mmol) of manganese dioxide to 1.4 g (34% of theory) of the title compound.

Mp: 160-162 ° C (ethyl acetate).

Analogously to Example 30, the compounds listed in the following Table 5 were prepared:

Table 5

Pr. X, Y V / thžck (% theory) 1.1. (° C) 31 3-NO _2> H 11 189-92 32 2-CF ₃ , H 32 180-3 33 4-CF ₃ , H 52 139-42

Example 34

5-Cyano-4- (2,3-dichlorophenyl) -2-methyl-6-N-methylaminopyridine-3-carboxylic acid methyl ester

CH ₃

Analogously to Example 20, 3.5 g (10 mmol) of the compound of Example V were oxidized with 10 g (115 mmol) of manganese dioxide to 1.7 g (49% of theory) of the title compound.

Analogously to Example 34, the compounds listed in Table 6 are prepared:

Table 6

Pr. X, Y V / Heavy (% theory) 1.1. (° C) 35 3-NO _2> H 10 213-4 36 2-CF ₃ , H 64 128-31 37 4-Cl, H 40 152-4 38 4-CF ₃ , H 30 175-9 39 H, H 70 121-4

Claims (9)

PATENT CLAIMS Substituted 4-phenyl-6-amino-nicotinic acid derivatives of the general formula I CO ₂ R ¹ CH. In which A represents an aryl group having 6 to 10 carbon atoms or a pyridyl group which may optionally be up to three times the same or different substituted by cyano, nitro, halogen, trifluoromethyl or a straight or branched alkylthio or alkoxy of up to 6 carbon atoms each, R ¹ represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, R ² and R ³ are the same or different and represent a hydrogen atom or a straight or branched alkyl or acyl group of up to 6 carbon atoms, and D is nitro or cyano and their salts for therapeutic use. Substituted 4-phenyl-6-amino-nicotinic acid derivatives according to claim 1, characterized in that: A represents a phenyl or naphthyl group optionally substituted up to three times equally or differently with nitro, cyano, fluorine, chlorine, bromine or iodine, trifluoromethyl, phenyl or a straight or branched alkylthio or alkoxy group of up to 4 carbon atoms, R * represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, R ² and R ³ are the same or different and represent a hydrogen atom or a straight or branched alkyl or acyl group of up to 4 carbon atoms in each case, and D is cyano or nitro and salts thereof for therapeutic use. Substituted 4-phenyl-6-amino-nicotinic acid derivatives according to claim 1, of the general formula I in which: A represents a phenyl group which is optionally up to two times the same or differently substituted by nitro, cyano, fluorine, chlorine, bromine or iodine, phenyl, trifluoromethyl, methylthio or methoxy R ¹ represents a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, R and R are the same or different and are hydrogen or a straight or branched alkyl or acyl group of up to 3 carbon atoms each, and D is cyano or nitro and salts thereof for therapeutic use. T 4-phenyl-6-amino-nicotinic according to claims 1 to 3 as well as conventional pharmaceutical compositions. Medicaments, characterized in that they contain at least one 4-phenyl-6-amino-nicotinic acid derivative according to claims 1 to 3, as well as conventional pharmaceutical auxiliaries. Medicaments according to claim 4 for the treatment of cerebral diseases, characterized in that they contain at least one acid derivative 6-amino-5-cyano-2-methyl-4-phenyl-nicotinic, 6-amino-4- (4-chlorophenyl) -5-cyano-2-methyl-6-amino-5-cyano-2-methyl-4- (4-methoxyphenyl) 6-amino-5-cyano-2-methyl-4- (4-nitrophenyl) 6. Substituted 4-phenyl-6-amino-nicotinic acid derivatives of of formula I A * in Λ A ^R 'm in which r ² R ³ N ^z k. N CH, And it means aryl group (C 6 -C 10) carbon atoms; a pyridyl group optionally substituted up to three times the same or differently with cyano, nitro, halogen, trifluoromethyl or straight or branched alkylthio or alkoxy of up to 6 carbon atoms each, R ¹ represents a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, R ² and R ³ are the same or different and represent a hydrogen atom or a straight or branched alkyl or acyl group of up to 6 carbon atoms, and D represents a nitro or cyano group and salts thereof, with the exception of ethyl nicotinic acid ethyl ester, nicotinic acid ethyl ester and nicotinic acid ethyl ester. 7. A process according to claim 6, characterized in that the dihydropyridines of the general formula II ' wherein A, D, R ¹ , R ² and R ^{3 are} as defined above and R ⁴ is as defined above for R ¹ but does not represent a hydrogen atom, oxidize in an inert solvent with a typical oxidizing agent, preferably manganese dioxide, the products are also alkylated or acylated in the organic solvent and in the presence of a base and optionally ester hydrolyzed. Use of 4-phenyl-6-amino-nicotinic acid derivatives according to claims 1 to 3 for the manufacture of medicaments. Use of 4-phenyl-6-amino-nicotinic acid derivatives according to claim 1 for the manufacture of medicaments for the treatment of cerebral diseases.